This is the second resubmission application for a Clinical and Translational Science Award. We describe Penn State University's plan to transform our health research and education enterprise through the work of the Penn State Clinical and Translational Science Institute (CTSI). Throughout the University, the CTSI initiative has been greeted with great enthusiasm, broad support across colleges and campuses, and reaffirmation of our responsibility as a land grant University. The overarching goal of the Penn State CTSI is an engaged and responsive health science research and education enterprise that delivers on the promise of improved health. Starting with unique strengths in relevant biological, social and physical sciences, a culture and organizational structure that encourages collaboration across units, a tradition of engaging in problem-driven research, and strong connections to communities throughout Pennsylvania, we plan to achieve this by: 1) bolstering community alliances to strengthen trust, enhance awareness of disparities and ascertain needs; 2) cultivating new problem-driven interdisciplinary collaborations that go well beyond the traditional boundaries of biomedicine to address these needs, including partnering with industry; 3) sharing resources and promoting their most proficient use; 4) capitalizing on novel tools in information technology to collect, share and mine data, and disseminate new knowledge; and 5) educating a new generation of investigators, health professionals and community leaders who are fluent across disciplines, aware of ethical principles, sensitive to the community's needs, and able to apply their skills in partnership with others. Penn State has a rich track record of breaking down barriers and of strong support for interdisciplinary collaboration, and has committed major resources to the CTSI. In this amended application, a new leadership team in biomedical informatics has been empowered to expand infrastructure and develop new software solutions to study genetics, epigenetics and systems biology. The University has increased its already substantial health science investment in transformational technologies, innovative educational programs, and major interdisciplinary pilot project programs. Jointly with our community partners, and through the CTSA consortium, the Penn State CTSI will serve as a collaborative engine that will drive research initiatives geared to enhance wellness and better predict, preempt and treat disease in the people we serve.